Turning Enzyme Models into Model Enzymes in a Substrate-Tailored, Desolvated Active Site.

Once taken out of the active sites, the same functional groups used by enzymes for catalysis tend to lose their "magical" catalytic power in small-molecule enzyme models. We report a small-molecule enzyme model that activates a benzylic alcohol by a nearby amine for the nucleophilic attack of an activated ester. Only when the two groups are placed inside a substrate-tailored hydrophobic pocket can they display catalytic turnovers and even become reactive enough to hydrolyze amides catalytically near physiological conditions, a long-standing goal for synthetic protease mimics. These results suggest that the large gap between the innumerable catalytically incompetent small-molecule enzyme models made by chemists and true enzyme-like catalysts could be bridged by environmental engineering, which in this work enables a simple combination of a tertiary amine and an alcohol to replicate the catalytic properties of serine protease in hydrolyzing aryl amides with substrate specificity.